Heroin, cocaine, and alcohol addictions, alone and in combination, along with their multiple and frequent medical complications (including hepatitis B and C, AIDS, and psychiatric comorbidity) remain the major medical problems confronting our nation and much of the world. Effective treatments must be based on a fundamental understanding of the biological bases of each specific addictive disease, including the effects of chronic exposure to specific drugs of abuse and the interaction with environment and genetic factors. Our NIH-NIDA P60 Treatment Research Center, Treatment of Addictions: Biological Correlates, will continue to identify and study the dynamic molecular, neurobiological, and behavioral changes caused by heroin and cocaine. Research will focus on the endogenous opioid system, to elucidate its importance in the biological basis of addictive diseases, and interactions with related neurotransmitters and neuropeptides, emphasis on dopaminergic and glutamatergic systems, and stress-responsive systems. All laboratory and clinical research studies, and the Research Cores, have been developed on an interactive basis with thematic integration for the entire Center. Bidirectional translational research is a hallmark of the work of this Center. Findings from basic and applied clinical research are used to formulate specific hypotheses and develop novel animal models. Findings from laboratory research (such as vasopressin alterations) are applied into innovative clinical research. The specific research projects include: 1) studies of the effect of exposure, withdrawal, and re-exposure to heroin or cocaine, dynamic neurobiological adaptations in the opioid system underlying addictive-like behavioral changes; 2) effects of drugs of abuse on stress-responsive brain systems and hypothalamic-pituitary-adrenal axis function; 3) cocaine-induced synaptic plasticity in limbic brain regions; and 4) alterations in neuroendocrine stress responsivity in specific addictive diseases without or with codependency or comorbidity. Increasing effectiveness of existing treatments and developing novel treatments depends on expanding our insights into the molecular neurobiology of addictions, which is the primary goal of these projects, each utilizing five core resources, including a Research Training Core. Thematic integration and scientific interaction fosters synergism, which only a multidisciplinary center can provide.